A critical step in gallstone formation is precipitation of cholesterol crystals from bile supersaturated with cholesterol. Since the supersaturated state in bile is frequent in healthy man, lithogenicity is probably best defined by failure to maintain cholesterol in an aqueous micellar or metastable supersaturated state. Substances in bile which inhibit or accelerate cholesterol crystallization have not been adquately investigated. Preliminary observations suggest that drugs which are excreted in bile may influence these processes. Basic to an interpretation of the physical chemical characteristics of lithogenic bile is 1) a self-consistent model of the bile salt-lecithin mixed micelle and its perturbations by addition of cholesterol, and 2) clarification of the behavior of cholesterol in the metastable and liquid crystalline states. Accordingly, the aims of this proposal include: 1) investigation of the micellar molecular weights of the bile salt-lecithin and bile salt-lecithin-cholesterol mixed micelles by the light scattering technique; 2) determination of the effect of bile composition on cholesterol disposition and formation of liquid crystals and microcrystals over time, in in vitro analog bile, utilizing microfiltration techniques, light and polarized microscopy; and 3) investigation of the effects of endogenous and exogenous substances excreted in bile on these phenomena. It is recognized that a need exists for a combined interdisciplinary approach to accomplish these aims. These studies will critically examine phenomena of fundamental importance to gain an appreciation of the determinants of the lithogenicity of bile. They may contribute to alternative approaches to the prevention of cholesterol gallstone genesis and elucidate potential hazards of drugs excreted by the biliary route.